This thesis describes the development of methodology on expanding the scope and investigating the mechanism to enantioselective induction of the catalytic, asymmetric Interrupted Feist-Bénary (IFB) reaction. We demonstrate the development of a new IFB reaction using 4-hydroxycoumarin as the nucleophile to synthesize a highly functionalized hydroxydihydrofuranoid with 60 to 90% yield. Based on previous work on the IFB reaction, pyriminidinyl bis-quinidine cinchona alkaloids catalysts were screened in hopes of producing the IFB product with synthetically useful enantioselectivities. At this point, we found that the addition of a 6-methoxypyridin-2-yl group on the front group of the catalyst increased the enantioselectivity to 29% ee.
In order to further understand the IFB reaction, we have implemented computational studies into our work and reinvestigated the classic IFB reaction. We first gauged the effects on the 6-position of the pyrimidinyl ring and synthesized a new set of catalysts. It was discovered experimentally and computationally that a chlorine at the 6-position had the highest level of enantioselective induction followed by a methoxy then a quinidine. We then probed the effects of the front group through a series of competition reactions and computational studies, where we discovered each catalyst’s mechanism to inducing enantioselectivity. In this thesis, we will report that our cinchona alkaloid catalysts increase the energy of the Si face attack. However, certain front groups also lower the energy of the Re face attack to further increase enantioselectivity. Meanwhile, other, less effective, catalysts maintain the Re attack energy to be similar to the achiral pathway while destabilizing the Si attack., 2019, Old URL: https://wesscholar.wesleyan.edu/etd_hon_theses/2117, In Copyright – Non-Commercial Use Permitted (InC-NC)
This thesis describes the application of novel and existing cinchona-alkaloid catalyzed Interrupted Feist Bènary (IFB) reactions towards the total synthesis of two biologically active targets: the anticancer compound (-)-rocaglamide and the benzo[b]indeno[2,1-d]furanone Picornavirus inhibitor tetracyclic antiviral-1 (TA-1).
Part I presents our progress towards both targets via the classic highly enantioselective and diastereoselective IFB reaction. Towards rocaglamide, we activated the relatively unreactive ester moiety of the IFB product and perform side chain extension, required to close the cyclopentanone ring of the natural product. We also accomplished the activation of the IFB¿s benzylic C-H bond by Hartwig¿s mild C-H azidation. Towards TA-1, we constructed the tetracyclic core of the target via a required tertiary alcohol protection followed by tin-mediated cyclization.
Part II describes the discovery and optimization of the asymmetric IFB-like reaction between 1,2,3-indanetriones and substituted phenols. We found that the introduction of a substituted aryl ester at the ortho position of the 1,2,3-indanetriones leads to moderate enantioselectivities (up to 79% ee). The introduction of stoichiometric benzoic acid additive was key for obtaining excellent enantioselectivity (up to 93% ee). This new acid-assisted asymmetric IFB-like reaction was used to prepare a number of chiral cyclic hemiacetals, which are useful precursors towards TA-1 and its analogs., In Copyright – Non-Commercial Use Permitted (InC-NC)
Antifungal 8, which lacks a common name, has a core structure similar to GlaxoSmithKline's griseofulvin, a potent antifungal agent, and is able to treat various systemic fungal infections in humans with compromised immune systems, livestock, and even plants. Antifungal 8 has been previously synthesized through a stereochemically uncontrollable, photochemical intramolecular ring-forming reaction of a benzophenone derivative. The asymmetric total synthesis of antifungal Compound 8 involves using an organocatalyzed asymmetric reaction, "Interrupted" Feist-Benary reaction to induce chirality and preferentially yield one enantiomer of antifungal 8. Asymmetric total synthesis, which is attempted herein, of both enantiomers of antifungal 8 separately permits identification of the enantiomer with the stronger antifungal properties., 2013, Old URL: https://wesscholar.wesleyan.edu/etd_hon_theses/960, In Copyright – Non-Commercial Use Permitted (InC-NC)
The employment of newly discovered, catalytic, asymmetric, carbon-carbon bond forming reactions can allow compounds with various functionalities to be synthesized. Specifically, an antifungal compound referred to as antifungal 8, can be produced by such a scheme. The racemate of this species has only been previously made through a photochemical reaction of a benzophenone.1 Even in its racemic form, antifungal 8 has displayed promising antifungal activity, rivaling that of its parent compound, griseofulvin.1 Griseofulvin is a common antifungal drug that has been rated one of the most essential medicines by the World Health Organization. Since the racemate of antifungal 8 possesses biological activity that surpasses that of griseofulvin against several fungal strains, an asymmetric synthesis of antifungal 8 is desirable. After all, the isolated enantiomer will possess twice the biological activity of the racemate.2
The suggested multistep route for the synthesis of antifungal 8 includes two of the major components that are characteristic of these modern asymmetric reactions: an ?Interrupted? Feist-Benary reaction and an aromatization step. First, the nucleophile for the ?Interrupted? Feist-Benary reaction is synthesized in several steps; these steps include a silylation reaction, acetal formation, a Grignard reaction, and a Dieckmann condensation. The nucleophile then reacts with the synthesized electrophile, prepared through tosyloxylation of an acetophenone; this yields the ?Interrupted? Feist-Benary product. Thereafter, the compound is aromatized, tosylated, and reduced.
The species will then be chlorinated, the alkoxy group will be removed, the compound will undergo triflation, and it will be subjected to a double methylation.
The successful synthesis of antifungal 8 by this method will not only generate a useful, biologically active compound, but will aid in the understanding of modern, catalytic, asymmetric, carbon-carbon bond forming reactions. These contemporary reactions will then be employed more widely to produce compounds with various biological functionalities, including anticancer, antibiotic, and antiviral agents., 2018, Old URL: https://wesscholar.wesleyan.edu/etd_hon_theses/1950, In Copyright – Non-Commercial Use Permitted (InC-NC)
The National Cancer Institute estimated that in the United States in 2018, ~24,000 people would die of leukemia and ~60,000 new cases would be detected.1 Thus, discovering and synthesizing new antileukemic compounds is essential to allow treatment of this disease. Therefore, this thesis describes a novel, faster, cheaper, and greener route for synthesizing an antileukemic natural product found in low levels in the roots and stems of Aglia elliptifolia in southeast Asia.2 Rocaglamide’s significant anti-cancer activity relies heavily on its structural complexity, containing five stereocenters. While total syntheses of (-)-rocaglamide have been developed, all of the current total syntheses are long, have poor yields, and utilize expensive and very toxic compounds.2
Through an asymmetric organocatalytic Interrupted Feist-Bénary-like synthesis, the enantioselectivity of two substituted cinchona alkaloid-derived pyrimidine catalysts have been tested under various reaction conditions. After the reaction conditions were optimized, the phenyl-phenyl derived catalyst proves to be the most effective with an enantioselectivity of 45-51% enantiomeric excess at room temperature. Though high enantioselectivity has not yet been achieved, the phenyl-phenyl derived catalyst proves to be effective at room temperature independently of the solvent used to run the IFB-like reaction. Once a potential chiral organocatalyst yields an enantiomer at greater excess of rocaglamide’s core structure, we will have two controlled stereocenters that will facilitate the total enantioselective synthesis of rocaglamide. In developing this new synthetic pathway for the total synthesis of rocaglamide, we will not only provide new insight into green, synthetic chemistry but also enable sufficient quantities of potential low-cost therapeutic treatments., 2019, Old URL: https://wesscholar.wesleyan.edu/etd_hon_theses/2156, In Copyright – Non-Commercial Use Permitted (InC-NC)