Ce travail de thèse s’intéresse à la synthèse totale d'alcaloïdes de la famille des Lycorines, produits naturels isolés à partir de plantes des Amaryllidaceae qui possèdent de multiples activités biologiques. Leurs structures sont caractérisées par un squelette commun tétracyclique azoté : le galanthane. L’accès rapide au squelette galanthane a été développé via une étape clé de métathèse tandem cyclisante permettant d’obtenir deux cycles fonctionnalisés en une seule étape. La première partie de ce travail a conduit au développement d’une voie de synthèse asymétrique des (–)-α et (–)-β-lycoranes à partir d’un même intermédiaire, une sulfinylaldimine α-chirale, obtenue par réduction d’un N-sulfinylthioimidate α-chiral grâce à des conditions développées au laboratoire. La seconde partie de ce travail a porté sur la synthèse asymétrique de la (+)-kirkine, nécessitant une révision de la stratégie pour former le cycle B du squelette galanthane de manière précoce dans la synthèse. Nous avons réalisé la première synthèse totale asymétrique de la structure décrite de la (+)-kirkine. L’obtention des lycoranes et de la kirkine prouve la flexibilité ainsi que l'efficacité de la voie de synthèse, en particulier de l'étape clé de métathèse tandem et des N-sulfinylthioimidates comme intermédiaires clés. Cette voie est donc très prometteuse pour accéder à d'autres composés naturels de la famille des Lycorines. / This thesis work focuses on the total synthesis of alkaloids of the Lycorine family, natural products isolated from the plants of Amaryllidaceae, owning many biological properties such as anticancer, antiviral, antimicrobial or anti-inflammatory. Their structure is characterized by a nitrogen-containing tetracyclic galanthan skeleton. A fast access to the galanthan skeleton was developed by a key tandem ring closing metathesis step to obtain two cycles in a single step. The first part of this work concerns the development of an asymmetric synthetic pathway to obtain the (–)-α and (–)-β-lycoranes from a common central intermediate, an α-chiral sulfinylaldimine, obtained by reduction of the corresponding α-chiral sulfinylthioimidate. The second part of this work focuses on the asymmetric synthesis of (+)-kirkine, which required a strategy revision for the formation of the B cycle of the galanthan skeleton earlier in the synthesis. We have succeeded in realising the first asymmetric total synthesis of the described structure for (+)-kirkine. The asymmetric synthesis of lycoranes and kirkine proves the flexibility and efficiency of the synthetic route, in particular of the tandem metathesis step and the N-sulfinylthioimidates as key intermediates. This synthetic pathway is therefore very promising to obtain other natural products of the Lycorine family.

This thesis focuses on methodology development using N-sulfinyl metallodienamines and metalloenamines derived from Davis-Ellman N-sulfinyl imines. The application of these methodologies toward the total syntheses of (+)-epiibogamine and (+)-chimonanthine is described. The vinylogous aldol reaction of N-sulfinyl metallodienamines was first reported in 2017 in the total synthesis of (−)-albocycline. However, the diastereoselectivity of this reaction was found to be incorrectly reported. Mosher ester analysis and HPLC analysis with a chiral column were employed to determine the dr. The vinylogous aldol reaction was optimized. Studies on the mechanisms affecting stereoselectivity revealed that stereochemical erosion occurred using SnCl4 combined with LiHMDS, but not with NaHMDS or KHMDS. A (Z)-metallodienamine with metal chelated transition state was proposed and supported by DFT calculations to rationalize the stereochemical course of the reaction. Iboga alkaloids have been historically used for anti-addictive properties and recently brought more attention as potential drug candidates for neurological disorders. However, the complex isoquinuclidine fused azapine scaffold of Iboga alkaloids are challenging to synthesize. To construct the key chiral 2-aminocyclohexene intermediate and isoquinuclidine ring more efficiently, three new methods were explored. These included the domino-Michael/Mannich annulation of N-sulfinyl metallodienamines, the Diels-Alder reaction of N-sulfinyl imines, and the three-component domino-Michael/Michael/Mannich (DM3) annulation of N-sulfinyl metalloenamines. The DM3 reaction provided the 1-amino-2,4-diester scaffold to access isoquinuclidine in high yield (84−94%) and excellent diastereoselectivity (up to >95:5 dr). Chiral N-sulfinyl silylenamines, were introduced to serve as a surrogate for poorly reacting N-sulfinyl aldimines in the DM3 reaction. This silyl-modified DM3 reaction enabled the shortest asymmetric total synthesis of (+)-epiibogamine in 7 steps. This isoquinuclidine intermediate would also provide access to (+)-dihydrocatharanthine and other Iboga alkaloids in future studies. Oxidative enolate coupling, via radical intermediates, was used to construct 1,4-dicarbonyl scaffold from the reaction between two enolate nucleophiles. An oxidative coupling of N-sulfinyl metalloenamines was discovered having the ability to construct vicinal quaternary stereocenters in high diastereoselectivity (16:1 dr). To showcase this new methodology, the synthesis of dimeric indole alkaloids, (+)-chimonanthine, was investigated. A new class of compounds, bis N-sulfinyl amidines, were prepared as the potential oxidative coupling monomers for the synthesis of (+)-chimonanthine in future studies. / Chemistry

<p>An original palladium-catalyzed ring opening carbonylative lactonization of synthetic available hydroxycyclopropanols was reported to efficiently synthesize tetrahydrofuran (THF) and tetrahydropyran (THP)-fused bicyclic γ-lactones, two unique scaffolds often found in quite a few natural products. This new developed reaction features mild reaction conditions, good functional group tolerability, and the scale-up abilities. The synthetic application was demonstrated in a short total synthesis of (±)-Paeonilide. The THF-fused bicyclic γ-lactone products can be readily diversified into some medicinally important structures, which further broadens the application of this new carbonylation approach.</p> <p>The first total synthesis of Phleghenrine A was reported. This synthesis features an unprecedented inverse electron-demand Diels-Alder reaction and Tiffeneau-Demjanov ring expansion to rapidly construct bicyclo[3,2,2]-nonane core structure of Phleghenrine alkaloids. Two Diels-Alder adducts were synthesized, which were the synthetic precursors for divergent synthesis of Phleghenrine A and B, respectively.</p>

Lyconadin A is an alkaloid possessing a unique structure and antitumor activity. The total synthesis of Lyconadin A was proposed via an acyl radical cascade reaction. To investigate the possibility and stereoselectivity of the cascade cyclization, phenyl selenoester 16 was chosen as a model substrate to study the 7-exo-5-exo radical cyclization. A synthetic route to phenyl selenoester 16 was developed. The 7-exo-5-exo radical cyclization was found to occur with a high yield and excellent stereoselectivty. Attempts were also tried to synthesize another radical precursor 14 albeit with less success. A synthetic pathway to the synthesis of 14 as well as its potential use in the context of the synthesis of Lyconadin A was proposed.

Lyconadin A (1) is a structurally unique Lycopodium alkaloid with antitumor properties, isolated from the club moss Lycopodium complanatum. We are developing a synthetic route to 1 based on a novel 7-exo-trig/6-exo-trig acyl radical cascade cyclization. The synthesis of model acyl radical cascade precursor 23 will be presented. Key features of this synthesis include the suppression of competing elimination during the alkylation of a hindered phenethyl bromide and the use of a lactone as a precursor to a compound bearing two differentially protected primary alcohols. An account of our studies on the model acyl radical cascade cyclization (23 to 24 above) will also be given, including a stereochemical analysis of the product. Our findings have been applied to develop a more detailed stereoselective synthetic plan for Lyconadin A (1).

Acutumine is a tetracyclic alkaloid isolated from the Asian vine Menispermum dauricum with selective T-cell cytotoxicity and antiamnestic properties. We have developed a total synthetic route to this congested alkaloid, during which we also found a novel, stereoselective radical-crossover reaction that combines an intramolecular radical conjugate addition with a subsequent enolate hydroxylation. Key features of this synthesis also include a reagent-controlled diastereoselective ketone allylation, an anionic oxy-Cope rearrangement to form a congested quaternary sterocenter, a pyridine-mediated selective ozonolysis, and a Lewis acid promoted Michael-type cyclization.

The neoclerodane furanoditerpenoid family of natural products is a compelling target for a divergent total synthesis due to the complexity around their spirolactone-containing decalin core, the similarities between their functional groups, and biological activities that indicate a potential for future medicinal application. While being a relatively small molecule, the most structurally complex compound of the family, teucrin A, contains six stereocenters, five of which are contiguous. Our divergent synthesis route involves the stereo-controlled formation of a common decalin intermediate in four concise steps and 32% overall yield from commercially available starting materials. Additionally, desmethyl montanin A - an analog of montanin A missing its methyl group - can be produced from this key intermediate in one step and 95% yield, for a total of 30% yield over five steps. The dual-key step of this route consists of a Lewis acid-catalyzed Diels-Alder cycloaddition which stereo-selectively forms the spirolactone, followed by a gold-catalysed 6-exo-dig cyclization of the Diels-Alder adduct to complete the decalin core. The complementarity of these two steps is the focus of the synthesis, with the remaining steps for the formation of select neoclerodane natural products consisting of simpler classical chemistry, highlighting the potential for the creation of a large "unnatural" product library for applications such as drug candidate screening. Progress has additionally been made toward teucrin A, setting a cornerstone for future advancements to be made on this project. This concise synthesis advocates for the Barriault group's Diels-Alder/gold cyclization method of forming complex structural cores and will be applied to the total syntheses of other natural products in the future.

3,5-Dimethylorsellinic acid (DMOA)-derived meroterpenoids are an extensive natural product family with significant structural complexity and diverse biological activity. Their structures feature various fused, bridged, spirocyclic skeletons and unconventional stereochemistries with significant strain, especially the trans-syn-trans fused drimane system, and extensive oxidative, skeletal rearrangements. Despite a long isolation history and extensive biosynthesis studies and encouraging biological activities, chemical synthesis of those natural products appeared only recently compared with other well-studied diterpene families such as the ent-kauranes, daphanes, and tiglianes. Thus, this thesis will present our work as an incremental advancement on the total syntheses of DMOA-derived meroterpenoids. In Chapter 1, a thorough biosynthetic relationship of DMOA-derived meroterpenoid subfamilies is reviewed and the most updated isolation and syntheses are covered with the purpose to provide the reader an understanding and appreciation of the origin of the exceptional diversity of DMOA-derived meroterpenoids. In Chapter 2, three generations of routes towards DMOA-derived spiromeroterpenoid are discussed in detail. The oxidative [3+2] cyclization approach was found to generate several complex dimers and the simplicission core. Lessons learned therein pointed to a successful strategy. In Chapter 3, a successful fragment coupling strategy culminated in a concise, modular, and collective synthesis of five spiromeroterpenoid natural products. The synthesis features a sterically hindered bis-neopentyl 1,2-addition coupling/oxidative Michael addition/MHAT reduction sequence to rapidly construct the conserved spirocycle with full stereo-control. The gateway natural product asnovolin A was secured in deca-milligram amounts which laid the foundation for chemoenzymatic synthesis of the highly oxidized spiromeroterpenoid novofumigatonin. In Chapter 4, significant progress was made towards the synthesis of the complex meroterpenoid andiconin. We developed a late stage de novo construction of the dearomatized biosynthetic precursor. A biomimetic radical fragmentation [4+2] cascade was designed to establish the highly congested [2.2.2] octane core of the natural product. / 2026-03-15T00:00:00Z

First isolated in 1948 from the Trichothecium roseum fungus, trichothecenes are a diverse class of sesquiterpene natural products with the structures of over 250 congeners established to date. Their general structure consists of the tricyclic “trichothecene” core, marked by the C12,13 exocyclic epoxide and C9,10 olefin, with further structural complexity generated through esterification of macrolide chains to afford macrocyclic trichothecenes including verrucarin A. Owing to their complex structures and potent anticancer activity, trichothecenes have captured the attention of numerous academic groups since the 1970s, resulting in total syntheses of both non-macrocyclic and macrocyclic trichothecenes. The macrocyclic compounds exhibit increased potency, with recent biological studies suggesting involvement of novel molecular targets. The dissertation research described herein is focused on efforts toward the total synthesis of (–)-verrucarol, the flagship trichothecene natural product, and related trichothecene congeners. (–)-Verrucarol was the subject of six total syntheses throughout the 1980s, serving as an entry point for macrocyclic trichothecenes including verrucarin A. Compelled by the recent literature on insight into their therapeutic activity, we have established a concise route to the trichothecene core of verrucarol in eight steps. The construction of the tricyclic system is enabled by a novel samarium (II) iodide (SmI2)-mediated radical cyclization to an enol sulfonate to generate a complex oxabicyclo[3.2.1]octanone ring system. Significant synthetic efforts focused on a key late-stage olefin isomerization, which was ultimately accomplished through Mukaiyama-hydration and elimination. Furthermore, while significant synthetic efforts have gone into constructing the tricyclic trichothecene core, only a single successful, albeit lengthy, enantioselective synthesis of (–)-verrucarol has been reported. To evaluate the full therapeutic potential of trichothecenes, a concise asymmetric synthesis to access the prerequisite tricyclic core is needed. Herein, we report a Cr (III)-salen complex-mediated Diels-Alder cycloaddition of 4-pyrones and the simple diene, isoprene, for rapid access of an enantioenriched precursor for the trichothecene core. Future efforts and synthetic strategies to generate macrocyclic analogues for structure-activity-relationship studies are provided, as focused synthetic efforts to evaluate their clinical potential are sorely needed. / 2025-09-20T00:00:00Z

The tree and shrub species belonging to the Myrtaceae family are rich in structurally diverse meroterpenoids which possess anti-cancer, anti-malarial, anti-bacterial, anti-viral, and anti-inflammatory biological activities. Many of the natural products belonging to this family are derived from two common precursors: syncarpic acid and formyl phloroglucinol. The dissertation research described herein is focused on the total synthesis of two subclasses of natural products: syncarpic acid-derived meroterpenoids and formyl phloroglucinol meroterpenoids. The synthetic methodologies disclosed were developed to enrich the chemodiversity of these novel meroterpenoids by providing efficient access to such scaffolds and derivatives. Rhodomyrtusials A–C, the first examples of syncarpic acid-derived sesquiterpene meroterpenoids featuring a unique 6/5/5/9/4 fused pentacyclic ring system, were isolated from Rhodomyrtus tomentosa along with several biogenetically-related dihydropyran isomers. Two bis-furans and one dihydropyran isomer showed acetylcholinesterase (AChE) inhibitory activity. Herein, the bioinspired total syntheses of six isolates were achieved in six steps utilizing a reactive enetrione intermediate generated in situ from a readily available hydroxy-endoperoxide precursor are reported. Further evaluation of alkene reaction partners identified additional modes of reactivity for the enetrione, leading to the production of novel small molecule scaffolds. Furthermore, computational studies have identified a valid asynchronous, concerted pathway leading to the formation of the bis-furan containing natural products. Eucalyptusdimers A−C, three dimeric phellandrene-derived formyl phloroglucinol meroterpenoids featuring an unprecedented, fused skeleton between two phellandrene and two acylphloroglucinol subunits, along with one biogenetically related intermediate eucalyprobusone A, were isolated from the fruits of Eucalyptus robusta. These isolates also showed AChE inhibitory activity. A one-pot, three-component reaction was identified to achieve the synthesis of eucalyprobusone A and subsequent synthetic efforts towards eucalyptusdimers A and B via hetero-Diels Alder (HDA) [4+2] cycloaddition with known terpene, alpha-phellandrene are outlined. Initial efforts failed to promote the desired HDA cycloaddition, which led to alternate exploration of oxidative [4+2] cycloaddition chemistry. Using this revised strategy, the synthesis of several Eucalyptus metabolites including grandinol, euglobal IIc, and euglobal T1 was achieved. Future efforts and synthetic strategies to afford the eucalyptusdimers from these precursors are provided. / 2025-09-20T00:00:00Z