Graduate Thesis Or Dissertation


The development of aminal radicals for the synthesis of nitrogen-rich natural products Public Deposited

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  • Organic compounds which contain one or more nitrogen atoms are especially important as they are disproportionately represented among biologically active molecules. As a result, significant effort has been focused on the development of methods for the synthesis of nitrogenous molecules. We identified the aminal as an under-explored functional group. Despite the presence of the aminal functional group in several biologically active natural products which have attracted the attention of the synthetic community, no bond forming reactions of the aminal functional group had been described in the literature. This dissertation describes the development of two new carbon-carbon bond forming reactions utilizing aminal radical intermediates (carbon-centered radicals wherein the radical bearing carbon atom has two nitrogen substituents). Additionally, this document describes progress towards the application of aminal radicals in the context of the total synthesis of the alkaloid leuconoxine. The preliminary investigations centered on the generation of aminal radicals under peroxide initiated conditions similar to those previously reported for the generation of α-aminoalkyl radicals. The treatment of aminal containing molecules with di-tertbutyl peroxide in the presence of a radical acceptor (e.g. 1-octene) produced either a complex mixture of products, or no reaction. Aminal radicals were successfully formed from 2-iodobenzyl substituted N-acyl aminals by radical translocation reactions using AIBN and either Bu₃SnH or (TMS)₃SiH as a stoichiometric hydrogen atom donor. It was found that aminal radicals participate in inter- and intramolecular C-C bond forming reactions with electron deficient alkenes. Reactions in the presence of electron rich or unactivated alkenes did not lead to the desired bond formation, instead giving products of dehalogenation. The reaction of N-acyl aminals which contained carbon atoms bearing only one nitrogen atom were shown to selectively give the product of bond formation at the aminal carbon. Chemical yields of the radical translocation reactions were as high as 91%. It was demonstrated that the SmI₂ reduction of N-acyl amidines or amidinium ions in the presence of a proton source and an electron deficient alkene yielded products of C-C bond formation. Chemical yields of these transformations were as high as 99% and can lead to diastereoselectivities in excess of 20:1. Mechanistic investigations of this reactivity indicated that the reactions likely proceed through an aminal radical intermediate. The application of aminal radicals to the total synthesis of the alkaloid natural product leuconoxine has been investigated. It was envisioned that the SmI₂ induced reductive alkylation reaction of a simple bicyclic N-acyl amidine would rapidly construct the fully substituted aminal stereocenter present in the natural product. While similar amidines have been reported in the literature, no general strategy to access amidines of this type was known. Three distinct synthetic strategies towards the preparation of the desired bicyclic N-acyl amidine substrate were developed and investigated. The first strategy relied on the formation of the amidine using the intramolecular aza- Wittig reaction of an imide and an azide. Unexpectedly, these reactions produced a bis-amide product. Attempts to induce an intramolecular condensation reaction of the bis-amide to give the desired amidine were unsuccessful. The second strategy disconnected the desired bicyclic N-acyl amidine through an intramolecular Nacylaiton reaction of an N-aryl amidine. It was envisioned that the amidine could be prepared from a bimolecular condensation reaction of an aniline and a lactam derivative. All attempts to form the desired amidine functionality were unsuccessful. The third strategy depended upon an N-arylation reaction for the conversion of a known bicyclic N-acyl amidine to the desired substrate for the synthesis of leuconoxine. While the desired substrate has remained elusive, a model system of the key N-arylation reaction has successfully given the desired N-aryl-N-acyl bicyclic amidine product.
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