Callophycolide A is a meroditerpene isolated from Callophycus serratus, a Fijian red macroalgae. Callophycolide A has been shown to inhibit bacterial growth, and it exhibits moderate cytotoxicity against multiple human cancer cell lines. Most importantly, it exhibits moderate activity against Plasmodium falciparum, the dead- liest malaria-causing parasite to humans. Due to its antimalarial action and the need for antimalarial drugs on the pharmaceutical market, efforts toward a modular approach to the total synthesis of callophycolide A are presented that incorporate inexpensive, commercially available starting materials, offer gram-level scalability, and utilize known chemistry, including copper-mediated aryl allylation, hydrolytic kinetic resolution, base-promoted epoxide ring-opening, and the Steglich esterification. Once completed, this synthetic pathway can be used as a template for the total synthesis of other related marine natural products, such as the callophycols, callophycoic acids, and the bromophycolides. Callophycoic acids, also isolated from C. serratus, are the first examples of diterpene- benzoic acids observed in macroalgae. In addition, these acids, particularly callophycoic acids G and H, exhibit modest antibacterial activity. Although they are not strongly potent against malaria, they share a trans-decalin core identical to callophycols A and B, which are halogenated diterpene-phenols isolated from C. serratus that do exhibit modest antimalarial activity. Due to their identical core and their simpler structure (i.e., trisubstituted olefin tail), if a divergent total synthesis of callophycoic acids G and H can be established, it can serve as a template for synthesizing natural products that have been identified to be more potent against malaria, such as the callophycols, which are more complex in structure. Herein, a total synthesis of callophycoic acids G and H is investigated, which consists of a Wittig reaction, nucleophilic addition, and a bromonium-induced cation-pi cascade cyclization, and the progress toward the target molecules in the current study will be disclosed. To access chiral intermediates for the aforementioned metabolites, catalytic methods were sought. Hydrolytic kinetic resolution (HKR) resolves racemic epoxides using water as the nucleophile and is most often catalyzed by chiral Co(III)-salens. Previous studies have shown that the counter-ion of the Co(III)-salen has a direct effect on the rate of the HKR; when catalyzed by a 50:50 mix of (R,R)-Co(III)-salen-OH and (R,R)-Co(III)-salen-SbF6, the fastest HKR rates occurred. It has further been shown that the enantioselectivity is primarily associated with the reaction of (R,R)-Co(III)-salen-OH on the activated epoxide. Based on the aforementioned origin of selectivity, a catalyst containing a 50:50 mix of (R,R)-Co(III)-salen-OH and (±)-trans-Co(III)-salen-SbF6 could, in principle, give high activities and enantioselectivities for HKR comparable to a mixed counter-ion system containing both (R,R)-Co(III)-salens. In this dissertation, a series of experiments are described that demonstrate that highly selective catalysis is only achieved using 100% enantiopure ligand and that mixtures of (R,R)-Co(III)-salen and (±)-trans-Co(III)-salen yield lower activity and selectivity. Control experiments demonstrate that this is due to rapid counter-ion scrambling under the reaction conditions, precluding the possibility of effectively co-utilizing enantiopure (expensive) and racemic (inexpensive) catalysts with differing counter-ions. The mechanistic investigations resolving the counter-ion scrambling are consistent with the currently accepted mechanism for catalysis, involving cooperative activity of the two Co(III)-salen species that activate the epoxide and water in the reaction. Moreover, the application of HKR in the progress toward the total synthesis of callo- phycolide A will be highlighted and discussed.

L’objectif de ce travail étaient le développement de catalyseurs hétérogènes efficaces pour promouvoir des réactions asymétriques, en utilisant la polymérisation oxydante ou la formation de polymères de coordination. De nouveaux complexes de salen Co(III) chiraux modifiés par des groupements aromatiques sur les position 5, 5’ ont été préparés et testés dans le dédoublement cinétique hydrolytique (HKR) des époxydes terminaux en conditions homogènes. Ces complexes ont été ensuite engagés dans les polymérisations oxydantes électrochimiques ou chimiques, et une stratégie de copolymérisation a fourni des polymères chiraux très efficaces et stables pour catalyser l’HKR dans des conditions hétérogènes. Nous avons alors cherché à préparer un catalyseur capable de catalyser deux réactions en cascade, en copolymérisant deux complexes de salen portant des métaux différents. Pendant ces études, les complexes de salen Mn ont révélé leur participation active à la réaction d’HKR des époxydes terminaux catalysée par les complexes de salen Co(III), en augmentant l’excès énantiomérique du produit de façon significative. Les études mécanistiques ont été ensuite réalisées pour tenter de comprendre le rôle des complexes de Mn dans cette réaction. De plus, des complexes de salen fonctionnalisés par le groupement pyridine ou le groupement de type acide isophtalique ont été synthétisés. Ces complexes ont été utilisés pour préparer de nouveaux réseaux de polymères de coordination poreux chiraux (collaboration avec l’équipe LCI de l’ICMMO et l’Institut Lavoisier à Versailles), qui sont ensuite testés comme catalyseurs hétérogènes dans la réaction de Henry asymétrique et la réaction d’HKR. / The aim of this work was to prepare new chiral heterogeneous catalysts for asymmetric catalysis by oxidative polymerization of chiral organometallic complexes or by formation of chiral metal organic frameworks. New chiral salen Co(III) complexes modified by oxidizable aromatic groups at position 5,5’ have been prepared and tested as homogeneous catalysts in the Hydrolytic Kinetic Resolution (HKR) of terminal epoxides. These complexes have also been engaged into the oxidative electrochemical and chemical polymerization, and a copolymerization strategy has afforded very efficient and stable heterogeneous catalysts for the HKR. The idea of copolymerization has then been extended to the copolymerization of two salen complexes with different metals, which is expected to promote successively two different asymmetric transformations. During preliminary investigations, the salen Mn complexes have been found to be able to enhance the catalytic performance of salen Co(III) complexes in the HKR by increasing significantly the enantiomeric excess of the products. Mechanistic studies have thus been realized to understand the role of salen Mn complexes in this reaction. Besides, some chiral salen complexes functionalized by pyridine or isophtalic acid groups have been synthesized for the preparation of new chiral metal organic frameworks (collaboration with LCI of ICMMO and Institut Lavoisier of Versailles), which have also been tested in the asymmetric Henry reaction and the HKR as heterogeneous catalysts.