Synthesis and reactions of heterocycles in the context of rhodium carbenoid chemistry
Manning, James Robert
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The primary objective of this thesis was to explore the reactions of donor/acceptor substituted rhodium carbenoids, particularly in the context of heterocyclic chemistry. The first major section of this thesis was devoted to exploring the scope of a reaction termed the combined C-H activation/Cope rearrangement-elimination reaction. In the context of this project, a newly developed one-pot protocol was used to synthesize a wide variety of aryl- and heteroarylvinyldiazoacetates in good yields. The one-pot protocol was also scaled up (10 g scale) as an Organic Syntheses procedure. The newly synthesized vinyldiazoacetates were used to synthesize 1-substituted naphthalenes by the combined C-H/Cope-elimination reaction in good yields and >98% ee. This strategy was then extended to the enantioselective synthesis of 4-substituted indoles in 45-95% yield and >98% ee. Both the 1-substituted naphthalene and 4-substituted indole scaffolds were then used to synthesize sixteen analogues of the antidepressant duloxetine. These analogues were tested in the laboratory of Dr. Steven Childers for their binding affinities to the monoamine transporters as part of an ongoing program to develop new medications for the treatment of cocaine addiction. Several of the analogues were potent, exhibiting nanomolar binding affinities. The second major section of this thesis began with a first generation approach to the total synthesis of elisabethin C, a marine natural product from p.elisabethae . In this approach, a compound containing an isoxazole was envisioned as a key carbenoid substrate. The strategy was not successful but a very unusual compound was isolated from the reaction. The product was formally the result of the reaction of one equivalent of a vinyl carbenoid undergoing a tandem cyclopropanation/Cope rearrangement with the substrate and also a second equivalent inducing a ring expansion of the isoxazole at the N-O bond. This intriguing reaction was further explored with a variety of simple isoxazoles and benzisoxazoles and found to be quite general, producing 2 H -1,3-oxazines in good yields. The mechanism is believed to involve an isoxazole-carbene ylide intermediate. A one-pot synthesis of highly functionalized pyridines and dihydropyridines was then developed from the reaction of 3,5-disubstituted isoxazoles and vinyl carbenoids. A wide variety of vinyl diazo compounds and isoxazole structures were tolerated, producing pyridines in moderate to good yields.