Leveraging Lewis Acids and Visible Light for Method Development and Total Synthesis
Richardson, Alistair
2022
Abstract
The synthesis of natural products, pharmaceuticals, and organic materials has long driven much of the organic chemistry research conducted in both academic and industrial settings. Target directed synthesis often inspires the creation of new methodologies and acts as the ultimate proving ground for existing procedures. As the targets become more complex, methods must advance to enable their syntheses. Since chirality is integral to natural products and pharmaceuticals, developing new methods in asymmetric synthesis is of utmost importance. Originally, asymmetric synthesis was accomplished through the use of chiral pool reagents, but this has limitations based on availability. This realization gave rise to the field of asymmetric catalysis in which an achiral or racemic starting material undergoes an enantioselective transformation aided by a chiral catalyst. Many of these catalysts are transition metal based with chiral ligands of natural origin. However, since the enantioselectivity is conferred by a chiral ligand, these reactions are also limited by the scope of their availability. This limitation is perhaps most apparent when both enantiomers of a target structure are desired. In these instances, both enantiomers of the chiral ligand would be needed which may not be possible. Enantiodivergent catalysis, where a single chiral source is used to obtain either product enantiomer, represents an attractive yet underdeveloped alternative. During our labs work towards the total synthesis of lingzhiol, a meroterpenoid natural product isolated as a racemic mixture, we discovered a Lewis acid dependent enantiodivergent Michael addition. We then applied this method to the total synthesis of (–)- and (+)-lingzhiol (Chapter 1), both of which show promise as a potential treatment for renal fibrosis. Subsequent studies revealed the mechanism of this enantiodivergent reactivity (Chapter 2). In addition to asymmetric synthesis, the synthesis of heterocyclic compounds is strongly emphasized in many research programs. Nitrogen containing heterocycles are of particular importance because of their prevalence in pharmaceuticals. However, azetidines remains largely underrepresented, most likely because of the lack of efficient methods for their synthesis. While photochemical [2+2]-cycloaddition reactions between imines and alkenes, known as the aza Paternò-Büchi reaction, would potentially allow straightforward access to azetidines, this process has been hampered by competing reactivities of excited state imines. Using the tools of visible light photocatalysis, we developed an alternative approach relying on selective excitation of the alkene-coupling partner using triplet energy transfer (Chapter 3). This work inspired our labs interest in other 4-membered rings, such as cyclobutanes, which are featured in a number of biologically active natural products and could be made via a [2+2]-cycloaddition. Cochlearol B is unique among them because of its highly substituted cyclobutane ring containing three quaternary and one tertiary carbon. Isolated in 2014 from Ganoderma cochlear, cochlearol B is a meroterponoid with documented renoprotective activity. Herein, we report our 14-step synthesis of (+)-cochlearol B, enabled by an alkenyl Catellani reaction and visible light mediated [2+2]-photocycloaddition (Chapter 4). Azetidines are less common in natural products, but there are examples in the literature. Gelsemoxonine is a monoterpene indole alkaloid that contains an azetidine ring. Part of the family of Gelsemium alkaloids, gelsemoxonine is structurally related to many biologically active natural products. We envisioned applying our aza Paternò-Büchi method to the total synthesis of gelsemoxonine. Here, we report our progress towards that goal (Chapter 5).Deep Blue DOI
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Organic Chemistry Total Synthesis Natural Products Azetidines Photochemistry Asymmetric Catalysis
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