Date of Award
Doctor of Philosophy (PhD)
Radical cations are highly reactive intermediates which when formed can lead to a variety of interesting and efficient synthetic transformation. Electrochemical oxidations may be used to generate radical cations from electron rich, nucleophilic functional groups, triggering intramolecular cyclization reactions. These intramolecular anodic olefin coupling reactions are a powerful synthetic tool for coupling electron-rich olefins with a second nucleophile to form complex ring systems. However, they do not all work well. The main focus of this dissertation research is to diagnose the main causes of failed anodic olefin coupling reactions, devise new methods to overcome or circumvent these causes, and then demonstrate how these new methods may be applied to the synthesis of natural product ring systems.
First, a failed cyclization between an enol ether and an allylsilane to form a six-membered ring and a quaternary center was studied. The slow nature of this cyclization led to elimination of a proton next to the radical cation as well as general decomposition and polymerization. With these side reactions competing with the desired cyclization, we hoped to find a way to stop or slow down these pathways relative to the cyclization. We have demonstrated that one solution to this problem is using an enol ether with an alcohol tethered 2 carbons away as an initiating group that quickly traps the radical cation formed from the anodic oxidation. At low temperatures, the formed ketal stays cyclized and the radical intermediate allows for a cyclization to occur with minimal cationic side reactions.
Second, this same “tethered alcohol enol ether” methodology was applied to another difficult cyclization, involving the formation of a 7-membered ring between a furan and an enol ether to form a 5-7-5 tricyclic ring system. This cyclization also suffered from elimination and polymerization side reactions outcompeting the cyclization. A new efficient route to these tethered alcohol enol ether substrates using a “Michael-like” addition of a Grignard reagent to a ketal protected enone was developed in order to have ample substrate to study this quite complicated electrolysis reaction. With the tethered alcohol enol ether substrate, a small amount what appears to be cyclized product is present. However the major reaction pathway from this electrolysis is hydrogen atom abstraction by the ketal radical intermediate, followed by oxidation of the furan ring. In this case, the unwanted elimination reaction is avoided, but this new problem is introduced. It is likely that this particular reaction requires some conformational constraint to accelerate the cyclization reaction of the less reactive radical intermediate.
Third, a series of oxidative cyclizations in which carboxylic acids trapped radical cations were investigated to make lactones. It was discovered that these cyclizations typically proceed quite well, with little to no competition from Kolbe-like decarboxylation reactions. In the cases of styrene radical cations, however, yields of these oxidative cyclizations were governed by the rate of the second oxidation of the molecules, with ortho- and para-substitutents on the styrene aromatic ring increasing the rate of the second oxidation and giving better cyclization yields than for the meta-substituted or unsubstituted cases.
Finally, we have been working to demonstrate the viability of lignin solvolysis-derived monomers as a source of synthetic building blocks. Following the clean extraction of aromatic lignin monomers from raw sawdust, both classical and electrochemical methods were applied towards the construction of a variety of privileged natural product ring scaffolds, including electron-rich isoquinoline alkaloids, benzodiazepenes, anthraquinones, and indenones.
Chair and Committee
Vladimir Birman, Marcus Foston, Garland Marshall, John-Stephen Taylor
Perkins, Robert John, "Anodic Electrochemistry: Controlling the Reactivity of Radical Cation Intermediates" (2016). Arts & Sciences Electronic Theses and Dissertations. 883.